Genomic Profiling Reveals Germline Predisposition and Homologous Recombination Deficiency in Pancreatic Acinar Cell Carcinoma.

Abstract

To determine the genetic predisposition underlying pancreatic acinar cell carcinoma (PACC) and characterize its genomic features. Both somatic and germline analyses were performed using an Food and Drug Administration-authorized matched tumor/normal sequencing assay on a clinical cohort of 28,780 patients with cancer, 49 of whom were diagnosed with PACC. For a subset of PACCs, whole-genome sequencing (WGS; n = 12) and RNA sequencing (n = 6) were performed. Eighteen of 49 (36.7%) PACCs harbored germline pathogenic variants in homologous recombination (HR) and DNA damage response (DDR) genes, including <i>BRCA1</i> (n = 1), <i>BRCA2</i> (n = 12), <i>PALB2</i> (n = 2), <i>ATM</i> (n = 2), and <i>CHEK2</i> (n = 1). Thirty-one PACCs displayed pure, and 18 PACCs harbored mixed acinar cell histology. Fifteen of 31 (48%) pure PACCs harbored a germline pathogenic variant affecting HR-/DDR-related genes. <i>BRCA2</i> germline pathogenic variants (11 of 31, 35%) were significantly more frequent in pure PACCs than in pancreatic adenocarcinoma (86 of 2,739, 3.1%; <i>P</i> < .001), high-grade serous ovarian carcinoma (67 of 1,318, 5.1%; <i>P</i> < .001), prostate cancer (116 of 3,401, 3.4%; <i>P</i> < .001), and breast cancer (79 of 3,196, 2.5%; <i>P</i> < .001). Genomic features of HR deficiency (HRD) were detected in 7 of 12 PACCs undergoing WGS, including 100% (n = 6) of PACCs with germline HR-related pathogenic mutations and 1 of 6 PACCs lacking known pathogenic alterations in HR-related genes. Exploratory analyses revealed that in PACCs, the repertoire of somatic driver genetic alterations and the load of neoantigens with high binding affinity varied according to the presence of germline pathogenic alterations affecting HR-/DDR-related genes and/or HRD. In a large pan-cancer cohort, PACC was identified as the cancer type with the highest prevalence of both <i>BRCA2</i> germline pathogenic variants and genomic features of HRD, suggesting that PACC should be considered as part of the spectrum of <i>BRCA</i>-related malignancies.